US20030153089A1 - Screening crystallization conditions of organic compounds - Google Patents

Screening crystallization conditions of organic compounds Download PDF

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Publication number
US20030153089A1
US20030153089A1 US10/340,573 US34057303A US2003153089A1 US 20030153089 A1 US20030153089 A1 US 20030153089A1 US 34057303 A US34057303 A US 34057303A US 2003153089 A1 US2003153089 A1 US 2003153089A1
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analyte
composition
crystallization
conditions
compositions
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US10/340,573
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Maxim Kuil
Philippus Hoedemaeker
Jan Abrahams
Ian Maxwell
Jasper Plaisier
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Universiteit Leiden
Avantium International BV
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Universiteit Leiden
Avantium International BV
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Assigned to UNIVERSITEIT LEIDEN, AVANTIUM INTERNATIONAL B.V. reassignment UNIVERSITEIT LEIDEN ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ABRAHAMS, JAN PIETER, HOEDEMAEKER, PHILIPPUS JACOBUS, KUIL, MAXIM EMILE, MAXWELL, IAN ERNEST, PLAISIER, JASPER RIKKERT
Publication of US20030153089A1 publication Critical patent/US20030153089A1/en
Abandoned legal-status Critical Current

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N23/00—Investigating or analysing materials by the use of wave or particle radiation, e.g. X-rays or neutrons, not covered by groups G01N3/00 – G01N17/00, G01N21/00 or G01N22/00
    • G01N23/20—Investigating or analysing materials by the use of wave or particle radiation, e.g. X-rays or neutrons, not covered by groups G01N3/00 – G01N17/00, G01N21/00 or G01N22/00 by using diffraction of the radiation by the materials, e.g. for investigating crystal structure; by using scattering of the radiation by the materials, e.g. for investigating non-crystalline materials; by using reflection of the radiation by the materials
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y40/00—Manufacture or treatment of nanostructures
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/02—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor using a plurality of sample containers moved by a conveyor system past one or more treatment or analysis stations
    • G01N35/028—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor using a plurality of sample containers moved by a conveyor system past one or more treatment or analysis stations having reaction cells in the form of microtitration plates

Definitions

  • the present invention relates to methods for crystal forms (polymorphs) for analytes using, for example, a method and an apparatus for screening the phase behavior, more in particular, crystallization behavior in liquid, gel or solid phases of such analytes, such as organic molecules, for instance, pharmaceutically interesting compounds and complexes, oligomers, salts, esters and solvates thereof, organometallic molecules such as catalysts for homogeneous catalysis, etc.
  • the invention also relates to the parallel detection of phase transitions, more specifically crystallization, of these analytes.
  • the invention also provides methods for producing crystals of analytes on any desired scale using the conditions identified according to the invention. Further uses of the crystals and compositions comprising such crystals are also disclosed. Crystals of analytes according to the invention can also be used to collect information on the structure of analytes, more in particular in relation to the existence of crystal polymorphism. The invention provides for a method for the rapid determination of crystal polymorphism.
  • Crystallization is, in general, considered as the separation or precipitation out of a liquid environment.
  • the basic approach to crystallization is usually fairly simple.
  • the molecule to be crystallized is dissolved or suspended and subsequently subjected to conditions that affect the solubility of the molecule in solution. This can be achieved by removal of the solvent or by the addition of other compounds that reduce the solubility, optionally in combination with variation of other factors such temperature, pressure or gravitational forces.
  • the conditions are right, small nuclei will form from which crystals will grow.
  • the optimization of the crystallization conditions is largely based on trial and error. To determine the optimal crystallization conditions can therefore be a laborious and time-consuming process.
  • the crystallization behavior of a compound is determined mostly by its stereochemistry. This obviously comprises its covalent bonding pattern but also its ionic structure as determined by the presence of any available counter-ions in the crystal lattice.
  • other external parameters also affect the crystallization of organic compounds such as concentration of the compound in the mother liquor, hydrophobicity/polarity of the solvents, temperature, speed of crystal formation (nucleation), pressure and many others.
  • the invention provides improvements in determining crystallization conditions in general and, in particular, in determining polymorphic behavior.
  • the invention further intends to overcome the above-mentioned disadvantages of the conventional techniques.
  • the present inventors have found a method for the screening of a large number of crystallization conditions. Further, they have devised a way for the screening of a large number of crystallization conditions in parallel and for the identification of crystal polymorphs.
  • a method and an apparatus for generating and analyzing, preferably in parallel, multiple crystal forms (polymorphs) of chemical substance or mixtures of substances (the analyte) from which preferably at least one crystal form is known.
  • an array of solutions, or at least one solution is provided, for instance, in a range of solvents or solvent mixtures, or at least one solvent.
  • the analyte may be provided in a specially designed substrate, but a conventional substrate such as a microtiter plate may suffice provided that some conditions are fulfilled which are exemplified in the various embodiments.
  • Conditions under which the analytes are kept in the substrate are changed, for instance, by altering or modifying physical or chemical conditions such as lowering the temperature or allowing solvent to evaporate.
  • the crystallization of the analytes may be induced by a change in these physical or chemical conditions.
  • the insoluble material is analyzed, for instance, by X-ray diffraction techniques and preferably in transmission geometry.
  • the analysis of the insoluble material can be performed in situ on the substrate or by transferring the insoluble fractions of the analytes to a carrier.
  • the X-ray diffraction patterns are, preferably automatically, corrected and compared. The patterns of different analytes are compared, thereby allowing the identification of different polymorphs and the conditions under which these polymorphs form or are converted from one polymorphic form into another.
  • the invention in one aspect relates to a method for detecting polymorphism of at least one analyte, comprising the provision of a set of compositions comprising at least one analyte and inducing or allowing each composition to adopt at least a first condition possibly influencing crystallization and detecting any crystallization in at least one composition.
  • An analyte within the terms of the present invention is a compound of which the crystallization behavior is to be determined.
  • An analyte in terms of the invention is a chemical substance or a mixture of different substances of which substance at least one crystal form is known or of which it is expected that at least one crystal form exists.
  • An analyte in terms of the invention is preferably an organic or organometallic molecule or compound, such as a pharmaceutically active molecule or catalyst-ligand complex or a dimer, salt, ester or solvate thereof.
  • an analyte in terms of the present invention can also be a biomolecule, i.e., nucleic acids, DNA's, RNA's, PNA's, polypeptides, peptides, glycoproteins and other proteinaceous substances, lipoproteins protein-nucleic acid complexes, carbohydrates, biomimetics, etc.
  • a biomolecule i.e., nucleic acids, DNA's, RNA's, PNA's, polypeptides, peptides, glycoproteins and other proteinaceous substances, lipoproteins protein-nucleic acid complexes, carbohydrates, biomimetics, etc.
  • FIG. 1 The overall layout of the microplate substrate with 96 containers.
  • FIG. 2 Filter holder.
  • FIG. 3 X-Y translation table on diffractometer.
  • FIG. 4 X-ray diffraction patterns of different polymorphs recorded in the microarray.
  • FIG. 5 X-ray powder diffraction patterns of polymorphs A, B and C of F 5 O 3 NC 18 H 2 .
  • FIG. 6 Pathways used to produce polymorphs B and C in bulk from polymorph A of F 5 O 3 NC 18 H 2 .
  • FIG. 7 Microwell containing a polymorph of F 5 O 3 NC 18 H 2 .
  • One preferred way of working the method of the present invention comprises providing a substrate comprising an array of optionally sealable containers, which containers are optionally provided with means to induce crystallization, such as substances that alter or influence crystallization behavior such as nucleation agents, depositing separate volumes of analytes in the form of solids, slurries, emulsions or solutions and whereby the composition of each container differs in at least one aspect from the composition of at least one other container, optionally sealing off the containers from the atmosphere, optionally providing the containers with an atmosphere that influences the crystallization behavior, allowing crystalline material to form, manipulating the obtained crystalline material diffraction, for instance, by removal of the solvents or providing the crystalline material on a carrier material to allow for analysis of the crystalline structure, preferably by X-ray diffraction techniques, preferably automatically determining the X-ray diffraction patterns of optionally selected analytes or compositions, optionally comparing the diffraction patterns of the analytes or compositions, optionally
  • the substrate is preferably chemically inert to the substances and solvents employed and is preferably transparent to the detection technique used, e.g., X-ray transparent in case of X-ray diffraction technique. If the substrate is not transparent to X-rays, the array of samples may be measured in reflection X-ray diffraction geometry, but preferably are measured in transmission X-ray diffraction geometry after transferring the samples sequentially, but preferably in parallel, to an X-ray transparent carrier.
  • the substrate is preferably also transparent to visual light (ca 200 nm to 1000 nm) to allow visual or optical inspection.
  • the substrate is preferably also capable of transferring heat, thereby allowing for temperature variations. Examples of arrays are 8 by 12 up to 32 by 48, with orthogonal center-to-center distance varying from 2 to 10 mm between the containers or wells of the substrate.
  • the determination of the polymorphic forms of the analyte is preferably achieved by electron diffraction or by X-ray diffraction technology. Different polymorphs of an analyte produce different diffraction patterns. By determining the diffraction patterns, preferably in transmission geometry, from the crystallized analytes and comparing these diffraction patterns, information is obtained relating the different crystallization conditions to different crystalline forms of the analyte.
  • the determination of the X-ray diffraction characteristics of the crystallized analytes can conveniently be carried out in the provided array in which the crystallization method has been carried out (in-situ).
  • this requires that the array itself is transparent to X-ray diffraction or that the background diffraction pattern from the array is determined and the obtained X-ray diffraction data from the crystal in the array are corrected for this background pattern.
  • An advantageous aspect of the present invention pertains to a method for optimizing the conditions of the transformation of one polymorphic form of an analyte into another polymorphic form by subjecting the one polymorphic form of the analyte to the method for detecting polymorphism of the present invention.
  • a plurality of different conditions is provided, each differing in at least one parameter which influences the crystallization behavior of the analyte to be crystallized.
  • the different conditions can be chemical or physical.
  • a chemical condition in general comprises different (concentrations of) solvents, buffers, precipitants, salts, etc.
  • a physical condition is seen in terms of temperature, pressure, etc.
  • Major advantages of the method according to the invention are that automated setup of the experiments is generally quicker for small volumes, the automated detection of crystals in an array of conditions is quicker as more samples can be tested simultaneously, less material is required thereby reducing wastage, more tests can be performed given the amount of material available, the chance that the conditions under which crystallization is achieved are identified significantly increases and the chances of identification of different polymorphic forms increases likewise.
  • a preferred way of providing a set of compositions for determining crystallization conditions for analytes is a method wherein a set of compositions is provided on a solid support medium comprising a multitude of separate cells, each comprising one composition.
  • an array-like test format is provided allowing for easy automation of dispensing compositions and/or changing conditions per composition and detection of phase change behavior (typically crystallization of the analyte).
  • the crystallization may be best achieved by a further change to the conditions by allowing changes in any of the parameters through diffusion, evaporation, temperature change or other techniques or processes and combinations thereof. Such further changes in physical or chemical conditions can be applied in the present invention and very conveniently so in the array format.
  • the cells on the solid support are preferably further equipped with means for controlling the atmosphere in or directly above the cells.
  • the support medium is, for instance fitted, with sealing devices or sealing substances which seal off the entire support or seal off individual cells or groups of cells.
  • sealing devices or sealing substances which seal off the entire support or seal off individual cells or groups of cells.
  • balls, plates, caps, inert liquids like paraffin oil, silicon oil, etc. can be provided.
  • the analyte is brought in the cells of the solid support by techniques that allow for the precise and controlled delivery of minute amounts of matter. Suitable techniques are those that allow for the precise and controlled delivery of amounts of liquids or solids in the range of microliters or -grams, preferably nanoliters or -grams, more preferable picoliters or -grams.
  • dispensing techniques such as piezo-electric dispensing techniques, bubble-jet dispensing techniques, electro-spray dispensing techniques, as well as other micro- and submicro-dispensing techniques can be used; preferably nano-dispensing techniques are used.
  • non-directional dispensing of a fluid onto the substrate for instance, by flood-filling by submerging the substrate into a fluid, pouring the fluid over the substrate, or other flood-filling techniques can be employed advantageously.
  • the analyte is provided by means of some carrier, for instance, in the form of a solution or emulsion, it is a preferred option to remove, at least partly, solvents and/or other carrier fluids by allowing or causing a degree of evaporation, drying, draining, lyophilization or other fluid removal technique from the cells.
  • the invention is particularly suitable.
  • a fast formation of nuclei can be designed, followed by slow crystallization on those nuclei, if desired.
  • Conditions on how to influence speed and growth and how to end crystallization can all be determined.
  • a production scale of crystals for instance, for pharmaceutical use (in pharmaceutical preparations) can be based on the conditions identified according to the invention.
  • gravity-induced convection that is caused by local concentration gradients that result from the accretion of molecules on the growing crystal can adversely affect the crystalline order of a crystal.
  • the method reduces gravity-induced convection during crystal growth, the crystalline order of crystals produced with the method will approach that of high quality crystals grown in space, i.e., in microgravity conditions.
  • the invention provides for the determination of crystallization conditions that allow for the growth of different crystal forms of the analyte, thus enabling the identification of polymorphic forms from the analyte.
  • This is valuable information, for instance, in the case of a pharmaceutical whereby polymorphs of the pharmaceutical compound of interest can each have different physical properties or different properties in terms of biological activity. Official approval such as from the United States Food and Drug Administration of a specific and well-defined drug cannot be transferred to another polymorph of the same drug, although the chemical nature of the constituting molecules is identical. It is, therefore, very important that the various polymorphs of a drug are discovered and identified in order to gain an understanding of their biological properties. Furthermore, the early discovery of these drug polymorphs is also pharmaceutically interesting as the different polymorphs may have a different biological activity, for instance, through differences in solubility.
  • the invention also provides a method for producing a composition comprising crystals of an analyte of a narrow size distribution, comprising selecting crystallization conditions for the analyte by a method according to the invention and scaling up the conditions to a desired total volume, where crystals obtained by the method can be used as nucleation centers.
  • the crystals obtained by such a method will be more homogeneous in size and composition than crystals obtained by methods available until now.
  • the invention also encompasses these crystals.
  • Such crystals can be used for pharmaceutical purposes or as seed crystals in further crystallization processes.
  • the invention provides a method for producing crystals of an analyte, comprising providing an oversaturated composition of the analyte and providing the oversaturated composition with seed crystals according to the invention.
  • a preferred use of the crystals produced according to the invention is in the determination of structures of analytes.
  • the invention further provides a method for determining the structure of an analyte comprising subjecting crystals from the composition according to the invention to solid-state NMR techniques, neutron diffraction, electron diffraction and/or X-ray diffraction and determining its crystal structure.
  • the method is carried out in an array of separate cells, whereby each cell contains a different composition.
  • each cell contains a different composition.
  • each combination may be provided in duplicate or triplicate on the same solid support medium.
  • any crystal that does not have a cubic symmetry is known to change the polarization of linearly polarized light, depending on its orientation with respect to the direction of polarization of the through-falling light.
  • This property of crystals and crystalline biomaterial in particular is at present being used to determine and inspect the quality of individual crystals.
  • this property can also be used to determine the presence or absence of a crystal of an analyte that is noncubic.
  • the change in phase behavior of the analyte is caused by the formation of crystalline material.
  • Changes in phase behavior can be determined in various ways, but for the rapid screening of multiple samples under reproducible circumstances, preferred techniques are based on the detection or measurement of, continuously or intermittently, optical and/or diffraction characteristics of the individual cells.
  • the determination of the optical and/or diffraction characteristics of the individual cells can be done with a system comprising:
  • a light source the direction of polarization of which can be varied
  • a holder for a substrate comprising a multitude of cells
  • a change in the polarization of the light generally corresponds to a change in phase behavior. It is preferred that the change in phase behavior is mainly due to a phase change of the analyte.
  • a change in phase behavior that is not caused by a phase change of the analyte may additionally provide useful and valuable information regarding the phase behavior of the analyte itself. For example, if any salt crystallizes, while the substance of interest remains soluble, the substance of interest cannot be precipitated at its present concentration with salt.
  • Detecting phase changes can also be done by visual screening, for instance, with the aid of microscopy techniques. The existence of polymorphs can then be determined by the previously described technique.
  • the invention further provides as a specific embodiment a method for screening the crystallization behavior of at least one analyte comprising the steps of:
  • the different cells can be compared (automatically) to each other.
  • the change in phase behavior of the composition is preferably mainly caused by a phase change, more in particular by crystallization, of the analyte.
  • an inert nucleus or inert nuclei for crystallization may be provided.
  • the invention thus provides a method wherein the surface of the support medium comprises at least one crystallization nucleus comprising an inert crystal, preferably those wherein the nucleation centers are in the form of small crystallites preferably of salts or complexes of the analyte.
  • the (crystalline) nature of the substrate itself may influence crystallization of the analyte.
  • the crystallization initiation may further be influenced by a step in which nucleation is induced by agitation, vibration, microwave treatment, (ultra)sonic treatments or a combination thereof.
  • a microbatch array designed to process organic and inorganic liquids at elevated temperature and pressure was used. Materials were chosen to be as chemically inert as possible to allow for a rapid heat transfer to and from the liquid compartments.
  • a microplate array with outer dimensions of 127.7 mm by 85.5 mm and containing 96 wells was machined from brass and was gold plated after machining. The volume of the microwells is approximately 50 ⁇ L and the individual wells are sealed with an O-ring made of a synthetic flexible polymer. For this purpose, VITON® rings were used, but chemically more inert rings like KALREZ® or TEFLON® rings might be preferable.
  • the wells were closed by covering the O-rings by a 4 mm thick glass plate (length 117 mm, width 75 mm).
  • a brass bracket is mounted with 16 small screws.
  • the format of the microplate array is based on the standard size of a 96-well microtitre plate.
  • the brass microplate is bolted to a stainless steel adapter board that fits snugly into the heating element of a commercially available 96-well thermocycler.
  • VITON is a registered trademark of DuPont Dow Elastomers LLC Corporation, and TEFLON and KALREZ are registered trademarks of E. I. duPont deNemours and Company.
  • the wells or containers of the substrate are filled with any manual, semi-automatic or automatic pipetting or dispensing device.
  • the analyte is introduced in solution, upon which the solvent can be evaporated. It may be important to thoroughly filter the solution of the analyte before introducing it in the containers. Subsequently, other components or solvents can be introduced by pipetting. If some or all of the analyte present in a container does not dissolve in its liquid environment, the temperature may be raised, optionally after the container has been sealed, to a temperature that is sufficiently high to achieve total dissolution.
  • a means of changing the conditions in the array of containers, resulting in crystallization of the analyte, is optionally provided.
  • a means of analysis of the crystallinity and identification of polymorphs in each of the solid fractions in the array of containers is provided.
  • the solid materials from each of the individual containers can be transferred simultaneously to a thin carrier membrane using one of a variety of different ways.
  • Whatman Polyfiltronics has developed a system for harvesting on a single filter precipitated chemicals from a 96-well plate by filtration using a special suction system.
  • a means of automated analysis and identification of physical properties of polymorphs on an array of containers is provided.
  • the optional filter is mounted on an X-Z translation system, like the one manufactured by Altechna Co. Ltd., Vilnius, Lithuania, that is placed on an X-ray diffractometer, like an FRG-391 generator from Nonius (Delft, NL).
  • X-ray diffraction patterns can be recorded on an area detector, like the MAR-345 image plate detector of MAR Research GmbH (Hamburg, Germany).
  • X-ray diffraction patterns are recorded of each of the retentates that are held on the filter.
  • the X-Z translation table moves the next retentate into the exposure position.
  • the X-ray diffraction images are analyzed and compared. Fluctuating backgrounds, due to, e.g., non-uniformity of the filter, can be removed from the diffraction images before mutually comparing the observed patterns.
  • a single chemical compound (F 5 O 3 NC 18 H 2 , molecular weight: 393.36) was tested for crystallizing conditions and polymorphism, using a simple heating-cooling cycle on a screen consisting of 16 different solvent compositions.
  • the diffraction patterns of different polymorphs were identified automatically using a cross-correlation method.
  • the full screen consisted of 6 identical subsets. The identified polymorphs are indicated in table I.
  • polymorphs B and C were produced from the original material, polymorph A, using a variety of pathways.
  • the formation of polymorph B was found after dissolving polymorph A in water at an elevated temperature of 120° C. and pressure. This seems to be an intermediate structure and several pathways could be used to obtain the polymorph C in bulk.
  • the X-ray diffraction patterns of the three polymorphs are given in FIG. 5.
  • both polymorphs B and C can be produced in bulk using different pathways as shown in FIG. 6.
  • the masses of polymorphs A and C were determined by ESI mass spectrometry and both masses were in agreement with the chemical composition as documented. It can be ruled out that polymorph B or C is a degradation product, since C can be produced from pure A via intermediate B.

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  • Chemical & Material Sciences (AREA)
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  • Analysing Materials By The Use Of Radiation (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Saccharide Compounds (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
US10/340,573 2000-07-13 2003-01-10 Screening crystallization conditions of organic compounds Abandoned US20030153089A1 (en)

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EP00202500.5 2000-07-13
EP00202500A EP1172646A1 (en) 2000-07-13 2000-07-13 Screening crystallisation conditions of organic compounds
PCT/NL2001/000541 WO2002006802A2 (en) 2000-07-13 2001-07-13 Screening crystallisation conditions of organic compounds

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EP (3) EP1172646A1 (ko)
JP (1) JP2004504596A (ko)
KR (1) KR20030038568A (ko)
AT (1) ATE465405T1 (ko)
AU (1) AU2001277811A1 (ko)
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DE (1) DE60141906D1 (ko)
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Cited By (2)

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US20030119060A1 (en) * 2001-08-10 2003-06-26 Desrosiers Peter J. Apparatuses and methods for creating and testing pre-formulations and systems for same
US20060051251A1 (en) * 2004-09-03 2006-03-09 Symyx Technologies, Inc. Substrate for sample analyses

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1308716A1 (en) * 2001-10-03 2003-05-07 Avantium International B.V. Method for performing a transmission diffraction analysis
DE10336110B4 (de) * 2003-08-06 2008-01-03 Proteros Biostructures Gmbh Vorrichtung und Verfahren zum Behandeln eines Proteinkristalls
WO2005105293A1 (en) * 2004-05-03 2005-11-10 Thar Technologies, Inc. Method and apparatus of screening polymorphs of a substance
WO2007037304A1 (ja) * 2005-09-28 2007-04-05 Dainippon Sumitomo Pharma Co., Ltd. 微量晶析装置及び微量晶析システム
WO2012142541A1 (en) * 2011-04-15 2012-10-18 Cornell University Single molecule imaging techniques to aid crystallization
CN115315299B (zh) * 2020-07-13 2024-06-04 日本碍子株式会社 精制方法

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US6296673B1 (en) * 1999-06-18 2001-10-02 The Regents Of The University Of California Methods and apparatus for performing array microcrystallizations
US20010036640A1 (en) * 2000-04-25 2001-11-01 D'amico Kevin L. System and methods for the high throughput screening of polymorphs
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US20020048610A1 (en) * 2000-01-07 2002-04-25 Cima Michael J. High-throughput formation, identification, and analysis of diverse solid-forms

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US6162530A (en) * 1996-11-18 2000-12-19 University Of Connecticut Nanostructured oxides and hydroxides and methods of synthesis therefor
US6371640B1 (en) * 1998-12-18 2002-04-16 Symyx Technologies, Inc. Apparatus and method for characterizing libraries of different materials using X-ray scattering
US6296673B1 (en) * 1999-06-18 2001-10-02 The Regents Of The University Of California Methods and apparatus for performing array microcrystallizations
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030119060A1 (en) * 2001-08-10 2003-06-26 Desrosiers Peter J. Apparatuses and methods for creating and testing pre-formulations and systems for same
US20060051251A1 (en) * 2004-09-03 2006-03-09 Symyx Technologies, Inc. Substrate for sample analyses
US7597852B2 (en) 2004-09-03 2009-10-06 Symyx Solutions, Inc. Substrate for sample analyses

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DE60141906D1 (de) 2010-06-02
WO2002006802A2 (en) 2002-01-24
DK1309851T3 (da) 2010-07-19
EP2194376A3 (en) 2012-04-25
EP1309851B1 (en) 2010-04-21
WO2002006802A3 (en) 2003-01-03
EP1309851A2 (en) 2003-05-14
AU2001277811A1 (en) 2002-01-30
IL153855A0 (en) 2003-07-31
CA2415561A1 (en) 2002-01-24
JP2004504596A (ja) 2004-02-12
EP2194376A2 (en) 2010-06-09
ATE465405T1 (de) 2010-05-15
EP1172646A1 (en) 2002-01-16
KR20030038568A (ko) 2003-05-16
ES2345319T3 (es) 2010-09-21

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